McAleer J J, McKeown S R, MacManus M P, Lappin T R, Bridges J M
Department of Haematology, Queen's University of Belfast, Northern Ireland.
Int J Radiat Oncol Biol Phys. 1992;23(3):551-5. doi: 10.1016/0360-3016(92)90010-f.
Hypobaric hypoxia has been used to induce tumor hypoxia for in vivo comparison of the anti-tumor effects of the bioreductive agents SR 4233 (3-amino-1,2,4-benzotriazine-1,4-dioxide), RSU 1069 (1(2-nitro-1-imidazolyl)-3-aziridino-2-propanol), and Nitromin (methylbis(2-chloroethyl)amine N-oxide). BDF mice bearing the T50/80 mammary carcinoma were treated with these agents over a range of doses under normobaric (oxic) and hypobaric (hypoxic) conditions. The time taken for the tumor to double treatment volume (volume doubling time) was used as a measure of anti-tumor effect. Volume doubling time was plotted against log dose and dose response curves were fitted. A dose enhancement ratio (the ratio of drug doses required to give an equivalent anti-tumor effect under oxic and hypoxic conditions) was determined. The dose enhancement ratios for SR 4233 and RSU 1069 were 8.8 and 8.5, respectively, showing that these agents had an equivalent and substantial enhancement of their cytotoxicity when combined with hypobaric hypoxia. For Nitromin, no significant dose response effect was obtained under oxic conditions precluding the calculation of the dose enhancement ratio. SR 4233 was found to have increased systemic toxicity when combined with hypobaric hypoxia, suggesting that it is more readily activated than the other drugs tested. This in vivo test system will allow determination of the dose enhancement ratio for novel bioreductive agents and facilitate their comparison.
低压缺氧已被用于诱导肿瘤缺氧，以在体内比较生物还原药物SR 4233（3-氨基-1,2,4-苯并三嗪-1,4-二氧化物）、RSU 1069（1-(2-硝基-1-咪唑基)-3-氮丙啶基-2-丙醇）和氮芥氧（甲基双(2-氯乙基)胺N-氧化物）的抗肿瘤作用。携带T50/80乳腺癌的BDF小鼠在常氧（常压）和低压（缺氧）条件下，用一系列剂量的这些药物进行治疗。肿瘤体积加倍所需的时间（体积加倍时间）被用作抗肿瘤效果的衡量指标。将体积加倍时间与对数剂量作图，并拟合剂量反应曲线。确定了剂量增强比（在常氧和缺氧条件下产生等效抗肿瘤效果所需的药物剂量之比）。SR 4233和RSU 1069的剂量增强比分别为8.8和8.5，表明这些药物与低压缺氧联合使用时，其细胞毒性有同等程度的显著增强。对于氮芥氧，在常氧条件下未获得显著的剂量反应效应，因此无法计算剂量增强比。发现SR 4233与低压缺氧联合使用时全身毒性增加，这表明它比其他测试药物更容易被激活。这种体内测试系统将有助于确定新型生物还原药物的剂量增强比，并便于对它们进行比较。
